Dobbelstein, Matthias

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Experimental Medicine"],["dc.bibliographiccitation.lastpage","289"],["dc.bibliographiccitation.volume","209"],["dc.contributor.author","Schulz, Ramona"],["dc.contributor.author","Marchenko, Natalia D."],["dc.contributor.author","Holembowski, Lena"],["dc.contributor.author","Fingerle-Rowson, Guenter"],["dc.contributor.author","Pesic, Marina"],["dc.contributor.author","Zender, Lars"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:13:28Z"],["dc.date.available","2018-11-07T09:13:28Z"],["dc.date.issued","2012"],["dc.description.abstract","Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF-HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF."],["dc.identifier.doi","10.1084/jem.20111117"],["dc.identifier.isi","000301943200009"],["dc.identifier.pmid","22271573"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10625"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/27181"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Rockefeller Univ Press"],["dc.relation.issn","0022-1007"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","37906"],["dc.bibliographiccitation.issue","35"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","37918"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Kosinsky, Robyn L."],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Hellbach, Nicole"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Mansouri, Ahmed"],["dc.contributor.author","Vogel, Tanja"],["dc.contributor.author","Begus-Nahrmann, Yvonne"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2019-07-09T11:42:03Z"],["dc.date.available","2019-07-09T11:42:03Z"],["dc.date.issued","2015-11-10"],["dc.description.abstract","Epigenetic regulatory mechanisms play a central role in controlling gene expression during development, cell differentiation and tumorigenesis. Monoubiquitination of histone H2B is one epigenetic modification which is dynamically regulated by the opposing activities of specific ubiquitin ligases and deubiquitinating enzymes (DUBs). The Ubiquitin-specific Protease 22 (USP22) is the ubiquitin hydrolase component of the human SAGA complex which deubiquitinates histone H2B during transcription. Recently, many studies have investigated an oncogenic potential of USP22 overexpression. However, its physiological function in organ maintenance, development and its cellular function remain largely unknown. A previous study reported embryonic lethality in Usp22 knockout mice. Here we describe a mouse model with a global reduction of USP22 levels which expresses the LacZ gene under the control of the endogenous Usp22 promoter. Using this reporter we found Usp22 to be ubiquitously expressed in murine embryos. Notably, adult Usp22lacZ/lacZ displayed low residual Usp22 expression levels coupled with a reduced body size and weight. Interestingly, the reduction of Usp22 significantly influenced the frequency of differentiated cells in the small intestine and the brain while H2B and H2Bub1 levels remained constant. Taken together, we provide evidence for a physiological role for USP22 in controlling cell differentiation and lineage specification."],["dc.identifier.doi","10.18632/oncotarget.5412"],["dc.identifier.pmid","26431380"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12736"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58576"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Usp22 deficiency impairs intestinal epithelial lineage specification in vivo."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","110879"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cell Reports"],["dc.bibliographiccitation.volume","39"],["dc.contributor.author","Giansanti, Celeste"],["dc.contributor.author","Manzini, Valentina"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Dickmanns, Achim"],["dc.contributor.author","Palumbieri, Maria Dilia"],["dc.contributor.author","Sanchi, Andrea"],["dc.contributor.author","Kienle, Simon Maria"],["dc.contributor.author","Rieth, Sonja"],["dc.contributor.author","Scheffner, Martin"],["dc.contributor.author","Lopes, Massimo"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-07-01T07:35:41Z"],["dc.date.available","2022-07-01T07:35:41Z"],["dc.date.issued","2022"],["dc.description.abstract","The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination.\r\nHowever, it also sustains the progression of DNA replication forks, even in the absence of functional p53.\r\nHere, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1\r\n(PARP1). When cellular MDM2 levels are increased, this leads to accelerated progression of DNA replication\r\nforks, much like pharmacological inhibition of PARP1. Conversely, overexpressed PARP1 restores normal\r\nfork progression despite elevated MDM2. Strikingly, MDM2 profoundly reduces the frequency of fork\r\nreversal, revealed as four-way junctions through electron microscopy. Depletion of RECQ1 or the primase/\r\npolymerase (PRIMPOL) reverses the MDM2-mediated acceleration of the nascent DNA elongation rate.\r\nMDM2 also increases the occurrence of micronuclei, and it exacerbates camptothecin-induced cell death.\r\nIn conclusion, high MDM2 levels phenocopy PARP inhibition in modulation of fork restart, representing a\r\npotential vulnerability of cancer cells."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1016/j.celrep.2022.110879"],["dc.identifier.pii","S2211124722006544"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112236"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-581"],["dc.relation.issn","2211-1247"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1411"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Landmann, H."],["dc.contributor.author","Proia, D. A."],["dc.contributor.author","He, S."],["dc.contributor.author","Ogden, F. L."],["dc.contributor.author","Kramer, Franz-Josef"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Moll, U."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:35:41Z"],["dc.date.available","2018-11-07T09:35:41Z"],["dc.date.issued","2014"],["dc.description.abstract","HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC(50)s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50 > 500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment."],["dc.description.sponsorship","Open-Access Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2014.378"],["dc.identifier.isi","000343162000012"],["dc.identifier.pmid","25210794"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10891"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32445"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to the heat shock protein 90 inhibitor ganetespib"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1634"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Kramer, Daniela"],["dc.contributor.author","Schoen, M."],["dc.contributor.author","Bayerlova, M."],["dc.contributor.author","Bleckmann, Annalen"],["dc.contributor.author","Schoen, Michael Peter"],["dc.contributor.author","Zoernig, M."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T10:01:17Z"],["dc.date.available","2018-11-07T10:01:17Z"],["dc.date.issued","2015"],["dc.description.abstract","The p53 family and its cofactors are potent inducers of apoptosis and form a barrier to cancer. Here, we investigated the impact of the supposedly inhibitory member of the apoptosis-stimulating protein of p53, iASPP, on the activity of the p53 homolog TAp73, and its cofactors p300 and CBP. We found that iASPP interacted with and stabilized the histone acetyltransferase p300 and its homolog CBP upon cisplatin treatment. Vice versa, iASPP depletion by shRNA resulted in decreased amounts of p300 and CBP, impaired binding of p300 and TAp73 to target site promoters, reduced induction of pro-apoptotic TAp73 target genes, and impaired apoptosis. Mechanistically, we observed that the p300-regulatory E3 ubiquitin ligase BRMS1 could rescue the degradation of p300 and CBP in cisplatin-treated, iASPP-depleted cells. This argues that iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination, thereby contributing to apoptotic susceptibility. In line, iASPP overexpression partially abolished the interaction of BRMS1 and CBP upon DNA damage. Reduced levels of iASPP mRNA and protein as well as CBP protein were observed in human melanoma compared with normal skin tissue and benign melanocytic nevi. In line with our findings, iASPP overexpression or knockdown of BRMS1 each augmented p300/CBP levels in melanoma cell lines, thereby enhancing apoptosis upon DNA damage. Taken together, destabilization of p300/CBP by downregulation of iASPP expression levels appears to represent a molecular mechanism that contributes to chemoresistance in melanoma cells."],["dc.description.sponsorship","Deutsche Krebshilfe; Wilhelm-Sander Stiftung"],["dc.description.sponsorship","Open Access Publikationsfonds 2015"],["dc.identifier.doi","10.1038/cddis.2015.17"],["dc.identifier.isi","000350575800008"],["dc.identifier.pmid","25675294"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11853"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37982"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","A pro-apoptotic function of iASPP by stabilizing p300 and CBP through inhibition of BRMS1 E3 ubiquitin ligase activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","452"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","458"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Lize, M."],["dc.contributor.author","Pilarski, S."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T08:45:16Z"],["dc.date.available","2018-11-07T08:45:16Z"],["dc.date.issued","2010"],["dc.description.abstract","E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. We identified E2F1-inducible microRNAs (miRNAs) by microarray hybridization and found that the levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1. High miR-449 levels were found in testes, lung, and trachea, but not in testicular and other cancer cells. MiR-449a/b structurally resemble the p53-inducible miRNA 34 family. In agreement with a putative tumor-suppressive role, miR-449a as well as miR-34a reduced proliferation and strongly promoted apoptosis by at least partially p53-independent mechanisms. Both miRNAs reduced the levels of CDK6, implying miR-449 in a negative feedback mechanism for E2F1. Moreover, miR-449a and miR-34a diminished the deacetylase Sirt1 and augmented p53 acetylation. We propose that both miRNAs provide a twofold safety mechanism to avoid excessive E2F1-induced proliferation by cell cycle arrest and by apoptosis. While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators. Cell Death and Differentiation (2010) 17, 452-458; doi: 10.1038/cdd.2009.188; published online 4 December 2009"],["dc.identifier.doi","10.1038/cdd.2009.188"],["dc.identifier.isi","000274565300008"],["dc.identifier.pmid","19960022"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6280"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/20395"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1350-9047"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10094"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.lastpage","10104"],["dc.bibliographiccitation.volume","68"],["dc.contributor.author","Braun, Christian J."],["dc.contributor.author","Zhang, X."],["dc.contributor.author","Savelyeva, Irina"],["dc.contributor.author","Wolff, Sonja"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schepeler, Troels"],["dc.contributor.author","Orntoft, Torben F."],["dc.contributor.author","Andersen, Claus L."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T11:07:54Z"],["dc.date.available","2018-11-07T11:07:54Z"],["dc.date.issued","2008"],["dc.description.abstract","microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNTAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microR-NtA that contributes to apoptosis and acute senescence. Here, we used array hybridization to rind that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest. [Cancer Res 2008;68(24):10094-104]"],["dc.description.sponsorship","NCI NIH HHS [R01 CA060664, R01 CA060664-13]"],["dc.identifier.doi","10.1158/0008-5472.CAN-08-1569"],["dc.identifier.isi","000261866800013"],["dc.identifier.pmid","19074875"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6279"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/52681"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.relation.issn","0008-5472"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13072"],["dc.bibliographiccitation.issue","15"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","13087"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Saini, Priyanka"],["dc.contributor.author","Li, Yizhu"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-11-22T14:31:35Z"],["dc.date.available","2021-11-22T14:31:35Z"],["dc.date.issued","2015"],["dc.description.abstract","The therapeutic efficacy of nucleoside analogues, e.g. gemcitabine, against cancer cells can be augmented by inhibitors of checkpoint kinases, including Wee1, ATR, and Chk1. We have compared the chemosensitizing effect of these inhibitors in cells derived from pancreatic cancer, a tumor entity where gemcitabine is part of the first-line therapeutic regimens, and in osteosarcoma-derived cells. As expected, all three inhibitors rendered cancer cells more sensitive to gemcitabine, but Wee1 inhibition proved to be particularly efficient in this context. Investigating the reasons for this potent sensitizing effect, we found that Wee1 inhibition or knockdown not only blocked Wee1 activity, but also reduced the activation of ATR/Chk1 in gemcitabine-treated cells. Combination of several inhibitors revealed that Wee1 inhibition requires Cyclin-dependent kinases 1 and 2 (Cdk1/2) and Polo-like kinase 1 (Plk1) to reduce ATR/Chk1 activity. Through activation of Cdks and Plk1, Wee1 inhibition reduces Claspin and CtIP levels, explaining the impairment in ATR/Chk1 activity. Taken together, these results confer a consistent signaling pathway reaching from Wee1 inhibition to impaired Chk1 activity, mechanistically dissecting how Wee1 inhibitors not only dysregulate cell cycle progression, but also enhance replicative stress and chemosensitivity towards nucleoside analogues."],["dc.identifier.doi","10.18632/oncotarget.3865"],["dc.identifier.fs","612801"],["dc.identifier.isi","000359009400018"],["dc.identifier.pmid","25965828"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13619"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/93390"],["dc.language","eng"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Impact Journals Llc"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.access","openAccess"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject","Wee1, ATR signaling pathway, replicative stress, checkpoint kinases, gemcitabine"],["dc.subject.mesh","Antimetabolites, Antineoplastic"],["dc.subject.mesh","Antineoplastic Combined Chemotherapy Protocols"],["dc.subject.mesh","Ataxia Telangiectasia Mutated Proteins"],["dc.subject.mesh","Cell Cycle Proteins"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Deoxycytidine"],["dc.subject.mesh","Drug Synergism"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Nuclear Proteins"],["dc.subject.mesh","Pancreatic Neoplasms"],["dc.subject.mesh","Protein Kinase Inhibitors"],["dc.subject.mesh","Protein Kinases"],["dc.subject.mesh","Protein-Tyrosine Kinases"],["dc.subject.mesh","Signal Transduction"],["dc.title","Wee1 is required to sustain ATR/Chk1 signaling upon replicative stress."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e980"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Schulz, R."],["dc.contributor.author","Streller, F."],["dc.contributor.author","Scheel, Andreas Hans"],["dc.contributor.author","Rueschoff, Josef"],["dc.contributor.author","Reinert, M. C."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Marchenko, N. D."],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:46:24Z"],["dc.date.available","2018-11-07T09:46:24Z"],["dc.date.issued","2014"],["dc.description.abstract","Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2013.508"],["dc.identifier.isi","000332222700004"],["dc.identifier.pmid","24384723"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9556"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34861"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-SA 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-sa/3.0"],["dc.title","HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S2589004222005636"],["dc.bibliographiccitation.firstpage","104293"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","iScience"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Stegmann, Kim M."],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Heinen, Natalie"],["dc.contributor.author","Blaurock, Claudia"],["dc.contributor.author","Karrasch, Tim"],["dc.contributor.author","Breithaupt, Angele"],["dc.contributor.author","Klopfleisch, Robert"],["dc.contributor.author","Uhlig, Nadja"],["dc.contributor.author","Eberlein, Valentina"],["dc.contributor.author","Issmail, Leila"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-06-01T09:40:16Z"],["dc.date.available","2022-06-01T09:40:16Z"],["dc.date.issued","2022"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1016/j.isci.2022.104293"],["dc.identifier.pii","S2589004222005636"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108685"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation.issn","2589-0042"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]